Although its effects are often quite mild, the von Willebrand's disease (vW'd) mutant gene is widely distributed in human patients and vW'd is the commonest hereditary hemorrhagic disorder yet no satisfactory hypothesis has been put forward to explain all the multiple defects which characterize this disease. It is very probable that the deficiency of factor VIII present in vW'd is the some way related to the other abnormalities and plays the key role in this disease. Factor VIII has a molecular weight exceeding 2 million and it may have unique properties and functions. Elucidation of the role of factor VIII in vW'd should throw some light on these. We propose to study the biochemical genetics of vW'd and hemophilia with particular reference to the factor VIII molecular abnormalities seen in both these diseases and determine the effect of this abnormality on certain platelet functions. We will first isolate the factor VIII protein from normal subjects, or its inactive analogue if present, in vW'd and hemophilia, and produce antibodies against these proteins. Using these and naturally occurring autoantibodies and various labeled antigens we will perform radioimmune and quantitative immunoelectrophoretic assays on different hemophilic and vW'd kindreds and on normal subjects. We will attempt to characterize the immunochemical expressions of factor VIII and its various intermediate and end stage degradation and catabolic fragments, establish quantitative and immunochemical specific assays for them and explore the in-vivo behavior of these fragments in experimental animals including normal and hemophilic dogs. We also propose to carry out other studies on vW's and hemophilic dogs. We will raise antibodies to normal dog factor VIII and the analogue protein in hemophilia and then use these to study vW'd and hemophilic kindred and also hemophilic and normal dogs who have been successfully transplated with normal or hemophilic organs, respectively.